The Functional Role of SEC23 in Vesicle Transportation,

Autophagy and Cancer

Jingchen Jing1, 2, Bo Wang1, 2, Peijun Liu1, 2,*

1Center for Translational Medicine, The First Affiliated Hospital, Xi'an Jiaotong University and 2The Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First

Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China

Correspondence to: Dr. Peijun Liu, Center for Translational Medicine, The First Affiliated Hospital, Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China. E-mail: liupeijun@mail.xjtu.edu.cn

1

Abstract

SEC23, the core component of the coat protein complex II (COPII), functions to transport

newly synthesized proteins and lipids from the endoplasmic reticulum (ER) to the Golgi

apparatus in cells for secretion. SEC23 protein has two isoforms (SEC23A and SEC23B) and

their aberrant expression and mutations were reported to cause human diseases and

oncogenesis, whereas SEC23A and SEC23B may have the opposite activity in human cancer,

for a reason that remains unclear. This review summarizes recent research in SEC23, COPII-

vesicle transportation, autophagy, and cancer.

Keywords: SEC23, COPII-vesicle transportation, autophagy, cancer

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Introduction

SEC23 is one of the components in the coat protein complex II (COPII) and regulates the

transportation of proteins and lipids from the endoplasmic reticulum (ER) to the Golgi

apparatus in cells. Approximately, one-third of all newly synthesized proteins will be

transported from the ER to the Golgi through COPII-coated vesicles [1]. The SEC23 protein,

as the core component of COPII, contains five distinct domains (i.e., the zinc finger, trunk

domain, β-barrel, α-helix, and gelsolin domain) and has two isoforms (SEC23A and

SEC23B). SEC23 is a GTPase-activating protein (GAP) that stimulates SAR1-GTP

hydrolysis in order to facilitate vesicle transportation in vivo [2], which activity could be

induced by SEC31 [3]. A previous study demonstrated that a SEC23B mutation causes

congenital dyserythropoietic anemia type-II (CDAII) [4], while the SEC23A mutation causes

cranio-lenticulo-sutural dysplasia (CLSD) due to abnormal endoplasmic-reticulum-to-Golgi

trafficking [5]. Aberrant expression was reported to be associated with human cancer

development, whereas SEC23A and SEC23B may have the opposite activity in human

cancer, for a reason that remains unclear [1]. Thus, in this review, we summarized recent

research involving SEC23, COPII-vesicle transportation, autophagy, and cancer development

and progression (Fig. 1).

Structure of SEC23

There are two isoforms of SEC23, namely SEC23A and SEC23B, to interact with SEC24

[6] and SEC16 [7, 8]. Both hSEC23A and hSEC23B have a molecular mass of approximately

85 kDa (765 vs. 767 amino acids) with 85% homology [9], exceeding 95% similarities

between mouse and human SEC23A and SEC23B. The functions of SEC23A and SEC23B in

the COPII complex were interchangeable in vivo [1]. The human SEC23A gene is localized at

chromosome 14q21.1 with 22 exons, while SEC23B is localized at chromosome 20p11.23

(https://www.genecards.org/). The SEC23 protein contains five distinct domains (i.e., the zinc

finger, trunk domain, β-barrel, α-helix, and gelsolin-like domain; Fig. 2) [10, 11]. The zinc

finger domain has 55 amino acids, containing a series of the zinc fingers that can interact

with RNA and DNA, while the trunk domain consists of 250 amino acids and is able to

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interact with Sar1 and the β-barrel domain consists of 180 amino acids and is essential to

form the inner coat. Moreover, the α-helical domain (with 105 amino acids) interacts with

Sar1 [12] and the 105 amino acid gelsolin-like domain is able to bind to the C-terminus of

SEC31, which shares the same triple-proline motifs with SEC16 [13], TANGO1, and

cTAGE5 [14, 15]. However, after we searched and blasted the functional domains of SEC23A

and SEC23B, we found that there are differences in the regions of their five functional

domains, like the Trunk domain, which could lead to some different functions between these

two proteins (Fig. 3). In contrast, these two proteins do have many identical regions and in

some situations, they may compensate each other in cells. Thus, these two proteins are

siblings, they do have differences in functions and expression in tissues; for example, the

level of SEC23B protein in the pancreas was higher by approximately nine folds than

SEC23A did, whereas SEC23A in the liver was much higher than SEC23B was. Thus, the

differential expression of these two isoforms in a given organ or tissue could lead to their

distinct phenotype or functions obviously.

SEC23 Regulation of COPII-vesicle Transportation

In normal eukaryotic cells, the ER functions to facilitate protein synthesis, folding, and

dispatch in the rough ER or lipid synthesis in the smooth ER [16]. The newly translated

proteins destined for secretion are transferred to the Golgi apparatus for post-translational

modification and then either transferred to different cell compartments or secreted into the

extracellular space [17], while lipids are also transported to other organelles or secreted [18].

However, before being transferred to the Golgi, they are selected and packaged into the

COPII to make COPII-coated vesicles [19, 20], and the COPII physically deforms the ER

membrane into vesicles and selects cargo molecules to transport them to the Golgi. To date,

the COPII is shown to consist of five proteins (i.e., SAR1, SEC23, SEC24, SEC13, and

SEC31). GTP-loaded SAR1, a small GTPase, will bind to the ER membrane and recruit the

SEC23/SEC24 complex to form the inner coat. The SEC23/SEC24 complex will recruit the

SEC13/SEC31 complex (the outer coat) for complete assembly of COPII [21]. After that, the

COPII-containing vesicles leave the ER membrane and SEC23 functions as GAP for SAR1

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dissociation from COPII [22], leading to the formation of the ER-Golgi intermediate

compartment, along which, the vesicles enter the Golgi apparatus [23]. This observation

indicates that SEC23 is a core component of COPII and is involved in the formation of the

inner coat by acting as a GAP and participating in cargo selection [7].

It is well established that the SEC23/SEC24 complex is recruited to the ER membrane by

SAR1, a small G protein, while SEC23A cycling can be altered by ER stress, which will

reduce the stability of SEC23 proteins and their binding to the ER membrane [24]. After

being recruited to the ER membrane, SEC23 will act as a GAP for SAR1, while SEC24 will

select and capture most of the cargo [25]. Indeed, a previous structural analysis study

demonstrated that the size of the COPII vesicles was usually between 60 and 100 nm and that

the size of the COPII vesicles bound to the concave surface of SEC23/SEC24 and SAR1 was

approximately 60 nm [11]. Moreover, SEC23, residing at the inner and outer coats, will

interact with SEC31, residing at the outer COPII coat, to form a SEC23-SEC31 interface in

order to recognize and capture various cargo molecules [26]. Molecularly, the Phe380 residue

of the SEC23 protein forms the binding groove to accommodate SEC31 interaction and

promotion of SEC23 GAP activity and COPII disassembly [27]. In addition, SEC23 can also

interact with the p150 dynactin subunit and the dynein motor in order to facilitate

microtubule-driven traffic from the ER-Golgi intermediate compartment [28, 29]. However,

other previous studies showed that Rab1b, localized at the ER-Golgi interface and the Golgi

[30, 31], was able to interact with SEC23 and change the kinetics of COPII

association/dissociation at the ER exit site [32].

Overall, SEC23 and the COPII-vesicle play an important role in the transportation of

newly translated proteins or lipids that are destined for secretion in cells. Indeed, during

cancer development and progression, a great number of proteins are produced and transported

in cancer cells, and SEC23B may play an important role in this process.

SEC23 Regulation of Embryo Development

Previous studies demonstrated that SEC23B played an essential role in mouse embryo

development, especially in the development of the secretory tissues, like the pancreas [33,

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34]. SEC23B-knockout mice died shortly after birth, due to the degeneration of the secretory

tissues [34]. SEC23B knockout not only led to an accumulation of proteins in the ER lumen

but also activated the apoptosis pathway in response to unfolded proteins (i.e., the ER stress

response) [34]. The mice with SEC23B deficiency had smaller pancreas than the wild-type

mice, and their pancreas structures also showed abnormalities, such as a lack of zymogen

granules in exocrine cells [33, 34]. In addition, a previous study showed that MIA SH3

Domain ER Export Factor 2 (MIA2) also participated in brain development [35, 36] and

protein secretion in embryos and loss of MIA2 expression affected the interaction between

SAR1 and SEC23, leading to the persistent SAR1 activation to interrupt COPII vesicle

formation and transportation from the ER to the Golgi in neurons [37]. Similarly, knockout of

SEC23A expression resulted in death of mice during embryonic stages with defects in

embryo and neural tube development [38].

Furthermore, it was reported that SEC23B was able to regulate cell growth. For example,

epidermal growth factor (EGF), functioning in cell growth and differentiation, can upregulate

SEC23B expression through the transcriptional regulator RNF11 [39]. EGF treatment was

able to induce the transportation efficiency of newly synthesized EGFRs from the ER to the

cell membrane by upregulation of SEC23B, SEC24B, and SEC24D [39]. This was an

important process for maintaining physiological levels of EGFR in cells, otherwise it could

lead to the proliferation of human cancer cells. It was also reported that SEC23 could directly

interact with the Trk-fused gene (TFG) through the TFG C-terminus in order to induce outer

coat dissociation [40]. TFG was implicated in multiple neurodegenerative diseases and

oncogenesis [40]; thus, SEC23 interaction with TFG could lead to tumor cell growth.

Thus, SEC23 could regulate embryo development, especially the secretory tissues and the

neural system. It could also promote cancer cell growth and inhibit cell apoptosis, indicating

that SEC23 may accelerate cancer development and progression.

SEC23 Mutations in Human Diseases

To date, various mutations associated with SEC23A and SEC23B were reported in human

diseases [10], although there was no two null SEC23B alleles occurring in patients, indicating

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that complete SEC23B deficiency could be lethal for cells [41]. Previous studies revealed

SEC23A mutations in CLSD, which is an autosomal recessive disease [5, 42]. CLSD patients

have craniofacial and skeletal malformations, associated with defects in collagen secretion [5,

42]. The germline SEC23A deletion in mice showed the same phenotype of human CLSD

[38], while SEC23A mutations in zebra fish jeopardized cartilage development [43].

On the other hand, SEC23B mutations could cause congenital CDAII in human beings,

which is an autosomal recessive disease. This disease is characterized by moderate anemia

and a lack of erythropoiesis [4, 44]. However, mice with complete SEC23B deficiency did

not show visible anemia or any of the characteristics of CDAII [34], although the mice would

be unable to survive after birth, probably because of hypoglycemia [34]. In contrast, insertion

of the SEC23A coding sequences into the murine SEC23B locus was able to rescue the lethal

SEC23B-deficient pancreatic phenotype completely in mice [1]. Furthermore, an increase in

SEC23A expression could also compensate for the function of mutated SEC23B in CDAII

patients, a potential therapeutic strategy for CDAII patients [45, 46]. In addition, SEC23B

mutations showed completely different phenotypes among humans, mice, and zebra fish [1].

In human tissues, SEC23B was mainly expressed in the bone marrow, whereas SEC23B was

strongly expressed in the mouse pancreas [13, 14] and disruption of SEC23B expression

showed defects in the secretion of extracellular matrix protein in zebra fish, which mimics

human CLSD [4].

Furthermore, approximately 3-9% of all thyroid cancer cases is a familial non-medullary

thyroid cancer (FNMTC), which may be due to Cowden syndrome [47], a rare autosomal

dominant familial cancer syndrome with a high risk of developing breast cancer,

metrocarcinoma, and non-medullary thyroid cancer [48]. A previous study of the whole

exome sequences in FNMTC revealed that SEC23B was a novel susceptibility gene in

Cowden syndrome and identified a heterozygous missense SEC23B variant (c. 1781T>G

[p.Val594Gly]) in a multi-generation Cowden syndrome family [49].

Therefore, both SEC23A and SEC23B have vital functions in human beings, loss of which

would cause serious diseases; particularly, lost SEC23B closely associated with Cowden

syndrome, which has potentially cancer predisposing.

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SEC23 Regulation of Autophagy in Cells

The transport protein particle (TRAPP) III complex could be recruited to the phagophore

assembly site of COPII during macroautophagy and bind to SEC23, providing the membrane

components to form the autophagosome and autophagy [50]. Moreover, SEC23 protein could

be phosphorylated by a serine/threonine protein kinase Hrr25 to trigger autophagy-related

pathways; however, if there is a loss of SEC23 expression, starvation-induced autophagy

could be impaired [51]. A previous study has demonstrated that autophagy was controlled by

a novel mechanism based on ULK-FBXW5-SEC23B action, showing that F-Box and WD

Repeat Domain Containing 5 (FBXW5) could inhibit biogenesis of the COPII-mediated

autophagosome by targeting and promoting SEC23B degradation in the presence of nutrients,

whereas ULK1 phosphorylated SEC23B at S186 and prevented SEC23B and FBXW5

interaction in order to inhibit SEC23B degradation during cell starvation, which in turn led to

cell autophagy [52]. The UNC51-like kinase 1 (ULK1) is an important enzyme in the

regulation of autophagy in mammalian cells [53, 54] and is activated after nutrient

deprivation through several upstream signals to initiate autophagy processes [55].

Interestingly, a mutation at the SEC23B S186 site, a cancer-related mutation occurring in

human melanoma, could abolish the interaction between SEC23B and FBXW5, resulting in

an increase in autophagy and promoting the survival of cancer cells [52].

Similarly, ULK1 can phosphorylate of SEC23A to decrease the interaction between

SEC23A and SEC31A and suppress the traffic from the ER to Glogi apparatus. Again, ULK1

can also phosphorylate SEC23A at the residues serine 207 and threonine 405 to induce cell

autophagy [56]. Interestingly, SEC23A and SEC23B are associated with autophagy, which is

involved in cancer development and progression.

SEC23 Alterations in Human Cancers

Thus far, we discussed the function of SEC23 in cells and its alterations and associated

mutations in human disease. This section will discuss the role of SEC23 in human cancer

development and progression, although previous studies revealed that SEC23A and SEC23B

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might have been opposing roles in cancer. In Table 1, we summarized the known miRNAs

that may directly affect SEC23 expression.

SEC23A Alterations in Human Cancer

To date, there is no report in PubMed showing SEC23A alterations in human cancer, but

the role of SEC23A in human cancer has been reported as a target of other genes, like

miRNAs (see below for details); thus, it remains to be determined how SEC23A regulates the

development of human cancer.

miRNAs are a class of small non-coding RNA molecules up to 24 nucleotides in length

and function to regulate cell proliferation, differentiation, apoptosis, and tumor metastasis by

downregulation of protein-coding gene expression [57]. A previous study reported that

SEC23A was the target gene of miR-200b, miR-200c, or miR-200s, miR-21, miR-375 [58-

62]. For example, miR-200 played an important role in the regulation of embryonic and

cancer stem cells and sensitivity of cancer cells to chemotherapy [63-67]. SEC23A is one of

the miR-200b targeting genes, which was inversely associated with prostate cancer tissues

[59]. Moreover, when miR-200c and miR-200s were overexpressed, SEC23A expression was

reduced [58, 60]. In addition, a recent study revealed that miR-21 expression enhanced

colorectal cancer cell proliferation and metastasis by targeting and inhibiting SEC23A

expression [68]. Furthermore, miR-375 possesses tumor-suppressive activity in different

human cancers [69]; for example, miR-375 was downregulated in invasive breast cancer,

leading to tumor cell migration and invasion [58, 70]. Another previous study reported that

miR-375 could target the expression of the SEC23A protein by binding to the 3'-

untranslatable region (3’-UTR) of SEC23A cDNA, while SEC23A expression was reduced in

primary prostate carcinoma tissues [61]. Furthermore, RNA binding motif 5 (RBM5)

functions to regulate gene transcription and mRNA splicing in cells and after knockdown of

RBM5 expression in neurons, the level of SEC23A mRNA was upregulated, although there

was no significant change in the level of the SEC23A protein [71].

Knockdown of SEC23A expression enhanced tumor cell proliferation and metastatic

colonization in prostate and colorectal cancer [58, 59, 61, 68]. It was possibly because

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SEC23A could mediate secretion of Insulin-Like Growth Factor Binding Protein 4 (IGFBP4),

a metastasis-suppressive protein [58]. Interestingly, SEC23A has a clear inhibitory role in

breast cancer metastasis, especially the step of colonization during tumor cell metastasis but

not at the step of tumor cell migration. Knockout of SEC23A could increase breast cancer

colonization and reduce tumor cell migration, where these two effects of SEC23A may cancel

each other out. In fact, endogenous SEC23A was lower in highly metastatic breast cancer

cells than in lowly metastatic cells. Consistently, SEC23A was also expressed at a lower level

in metastatic than in the primary tumors [60]. Taken together, both clinical and animal data

demonstrates that SEC23A plays a key role in the inhibition of breast cancer metastasis.

Furthermore, detection of miRNA-375 vs. SEC23A expression in thyroid carcinoma cells

was a useful biomarker to assess the in vitro efficacy of vandetanib, a selective kinase

inhibitor of the vascular endothelial growth factor receptor (VEGFR), the epidermal growth

factor receptor (EGFR), and the RET-tyrosine kinase [72]. SEC23A expression was also

reported to be associated with the resistance of prostate cancer to docetaxel treatment [73]. In

addition, SEC23A was used as a biomarker of pain flare in patients with painful bone

metastases [74].

SEC23B Alterations in Human Cancer

Previous studies revealed that germline heterozygous SEC23B variants were potentially

cancer predisposing, even though the mutant SEC23B (associated with ER stress-mediated

tumorigenesis) did not cause an overall decrease in SEC23B expression [49, 75]. Indeed, ER

stress is a hallmark of cancer [76, 77]. Other previous studies showed that alteration of

SEC23B was associated with the development of thyroid cancer [78], hepatocellular cancer

[79], and prostate cancer [80].

As a novel susceptibility gene in Cowden syndrome, the SEC23B variant (c. 1781T>G

[p.Val594Gly]) was able to promote proliferation, colony formation, survival, and invasion of

normal thyroid cells, which was associated with cancer predisposition induced by ER stress

[49]. Furthermore, another study demonstrated that SEC23B contributed to cancer

predisposition through the ribosome biogenesis pathway, independent of SEC23B-mediated

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COPII functions [75]. In addition, tandem mass spectrometry [79] compared the transitional

endoplasmic reticulum (tER) in the liver tumor nodules vs. the control rat liver and showed

that SEC23B expression was upregulated in tumor ER, and this differential SEC23B

expression suggests that SEC23B could be used as a potential novel tumor marker for

hepatocellular carcinoma [79].

In addition, SEC23B is shown to be a target of miR-130a and the latter was downregulated

in prostate cancer [80], whereas miR-130a overexpression in prostate cancer cells reduced

tumor cell proliferation and invasion capacity but induced apoptosis [80]. However,

knockdown of SEC23B expression mimicked the effect of miR-130a overexpression in

prostate cancer cells [80]. This study implies that SEC23B could be an oncogene in prostate

cancer. Based on these few studies, we concluded that SEC23B expression is frequently

upregulated in these types of human cancer and functions as an oncogene or possesses

oncogenic activity in these cancers. However, more stufdies are needed to clarify the role of

SEC23B in human cancer (Fig. 4).

Summary and Future Direction of Research on SEC23

To date, different studies have shown the importance of SEC23 participation and function

in COPII, particularly the SEC23/SEC24 complex, in order to facilitate newly translated

secretion proteins transferred from the ER to the Golgi apparatus for secretion. SEC23

interacts with SAR1 and SEC31 to select cargo and induce the GTPase activity of SAR1

during vesicle formation, leading to the secretion of proteins and lipids. Thus, as an important

member of COPII, SEC23B is involved in collagen secretion [81]. SEC23 is involved in

embryo development and SEC23B plays an essential role in mouse secretory tissue

development, whereas SEC23B mutations could lead to the death of the mice shortly after

birth. The main reason for this could be that the loss of SEC23 expression enhanced apoptosis

of the secretory tissues, like the pancreas, while SEC23 also plays a role in brain

development and function in mice. In addition, SEC23 affects on the transportation of EGFR

from the ER to the Golgi for cell proliferation.

Interestingly, the loss of SEC23B mainly affects the exocrine glands, not the endocrine

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tissues. The SEC23B-deficient mice also shows apoptosis in salivary gland and gastric

glands, which may be caused by ER stress pathways, such as PERK or other two ways. The

loss of SEC23A could also cause the death of mice embryos. And about half of the live

SEC23A-deficient mice embryos would appear neural tube opening at midbrain, which could

be found in all of the surviving and dead embryos. Besides, the deletion of SEC23A could

lead to the apoptosis in extraembryonic membranes, which may be also caused by ER stress,

just like SEC23B-deficient mice. Therefore, both SEC23A and SEC23B may have effect on

ER stress, especially the PERK pathway.

Furthermore, SEC23B can also help in the regulation of autophagy in cells because

SEC23B can be phosphorylated by ULK1, Hrr25, and TRAPPIII, all of which are in the

autophagy pathway. ULK1 can also phosphorylate of SEC23A and inhibit the traffic from ER

to Glogi. SEC23 was shown to be a master regulator of budding and fusion through the

phosphorylation-dephosphorylation cycle in order to facilitate the formation of the

autophagosome [f]. Autophagy is an evolutionarily conserved cellular process and its

alteration is involved in cancer development and progression [83, 84]. In vitro SEC23A

expression suppressed proliferation and metastasis of breast, prostate, and colorectal cancer

cells. In contrast, downregulated SEC23A expression was associated with poor disease

relapse-free survival (RFS) of breast cancer patients, indicating that SEC23A might be a

potential tumor metastasis suppressor. In addition, reduced SEC23A expression increased

sensitivity of medullary thyroid carcinoma to vandetanib treatment, all of which suggest that

SEC23A could be a tumor suppressor gene, indicating opposing roles for SEC23A and

SEC23B in cancer, although their role in cells is interchangeable in vivo.

However, additional research is needed to understand the precise function and role of

SEC23A and SEC23B in human disease and cancer development. Future study will analyze

their expression using online databases, like TCGA data, to find an association between

expression and different human cancers. Functionally, further study will investigate the gain

and loss of these proteins’ function in cells in order to better understand their role in

individual human cancers. Human cell lines remain one of the better models to study and

understand SEC23 activity in the context of human disease, while animal experiments could

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help us to assess the functional role of SEC23.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (#81872272).

Conflict of Interest

The authors declare that there is no conflict of interest in this work.

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Table 1 SEC23 as the target gene of miRNAs

miR Target Cancer type Ref.

miR-200b SEC23A Prostate [58]miR-200c SEC23A Prostate [57]

miR-200s SEC23A Breast [59]

miR-21 SEC23A Colorectal [67]

miR-375 SEC23A BreastProstate

[57][60]

miR-130a SEC23B Prostate [79]

Figure 1 SEC23 function in cell proliferation, autophagy, and apoptosis. As a core component

of COPII vesicles, SEC23 is not only involved in the protein transportation and secretion

process in cells but also participates in autophagy and promotes the survival of cancer cells.

Furthermore, SEC23B regulates development of the brain and pancreas in mice.

21

Figure 2 Illustration of SEC23 protein functional domains. (Modified from Lee and Miller

[10] and Yoshihisa et al. [11], using the tools from a previous study [85]). The SEC23 protein

contains five functional domains, i.e., the zinc finger, trunk domain, β-barrel, α-helix, and

gelsolin-like domain [10, 11].

Figure 3 Amino acid blast results of SEC23A and SEC23B. The five functional domains of

SEC23B [41] are labeled by different colors, while SEC23A could not be labeled for its

unknown domain location. Refer to the structure of SEC23 [12], the domain location of

ZNF

Trunk

β-barrel

α-helical

Gelsolin

22

SEC23A may be similar to SEC23B.

Figure 4 Opposite functions of SEC23A and SEC23B in human cancer. SEC23A was

expressed at a lower level in cancer tissues and cells, whereas SEC23B expression was often

higher in tumor than in normal tissues, indicating their opposite functions in cancer cells,

which effects were confirmed in tumor cell proliferation, metastasis, and colony formation.

23